Molecular Diagnosis of Severe Combined Immunodeficiency—Identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 Mutations in a Cohort of Chinese and Southeast Asian Children

Abstract

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

“…Its database stores clinical information provided by the referring doctors, laboratory results, and genetic test reports (12–14). From 2005 to 2016, 147 SCID patients were referred from 23 centers to the APIN for consultation and genetic testing, 42 of whom were reported in our previous study (13). In our study, we included patients with documented age at presentation (AP) and diagnosis.…”

“…Genetic analysis was performed in the Department of Pediatrics and Adolescent Medicine of the University of Hong Kong using PCR and direct sequencing (Table SE1 in Supplementary Material) (13). Genetic and functional studies on PID, data archival in the APIN database, and DNA storage were approved by the Clinical Research Ethics Review Board of the University of Hong Kong and Queen Mary Hospital (Ref.…”

Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing

“…Several splice site prediction programs predict disruption of the exon 2 splice donor site due to the c.221+2T>G mutation (Table S1). Furthermore, a similar mutation (heterozygous c.221+2T>A) together with a heterozygous missense mutation in IL7R was found by Lee et al in a patient with T-B+ SCID [23]. Thus, compound heterozygosity for these variants could be considered causative.…”

A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T−NK−B+)

“…Mutations in the X-linked IL2RG gene encoding γc causes more than 50 % of all SCID cases and mainly affects males; IL7R gene mutations result in at least 10 % of SCID cases and occur in both males and females (Buckley 2004). Previous studies have reported that certain unaffected people have missense homozygous IL7R gene mutations (Lee et al 2011). We suggest that in the case of our patient, X-SCID was not caused by an IL7R gene mutation, although CD127 expression in the patient was lower.…”